Abstract
Septic shock can increase pro-inflammatory cytokines, reactive oxygen species (ROS), and multiple organ dysfunction syndrome (MODs) and even lead to death. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been proven to exert potential antioxidant and anti-inflammatory effects. We investigated the effects of linagliptin on endotoxic shock and acute kidney injury (AKI) in animal and cell models. In the cell model, linagliptin attenuated ROS by activating the AMP-activated protein kinase (AMPK) pathway, restoring nuclear-factor-erythroid-2-related factor (Nrf2) and heme oxygenase 1 (HO-1) protein, and decreasing pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β)). In the animal model, 14-week-old conscious Wistar–Kyoto rats were randomly divided into three groups (n = 8 in each group). Endotoxin shock with MODs was induced by the intravenous injection of Klebsiella pneumoniae lipopolysaccharide (LPS, 20 mg/kg). Linagliptin improved animal survival without affecting hemodynamic profiles. In the histopathology and immunohistochemistry examinations of the rat kidneys, linagliptin (10 mg/kg) suppressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inducible nitric oxide synthase (iNOS), decreased injury scores, and preserved E-cadherin expression from LPS damage. In conclusion, linagliptin ameliorated endotoxin-shock-induced AKI by reducing ROS via AMPK pathway activation and suppressing the release of TNF-α and IL-1β in conscious rats.
Highlights
Sepsis, an immune response to infection, has a complex pathophysiology and is associated with an increased risk of acute kidney injury (AKI)
Decreased global renal blood flow, ischemia-reperfusion damage, and following renal tubular epithelial cell (TEC) death have been recognized as the prevailing pathophysiology of sepsis-associated AKI (S-AKI), accumulating evidence suggests that additional mechanisms must be at play [5,6]
In the reactive oxygen species (ROS) assay, linagliptin demonstrated better suppression of the intensity of dichlorodihydrofluorescein diacetate (DCF-DA) fluorescence augmented by 12 h LPS treatment (Figure 1A,B)
Summary
An immune response to infection, has a complex pathophysiology and is associated with an increased risk of acute kidney injury (AKI). The annual global incidence of sepsis-associated AKI (S-AKI) is estimated to be approximately 1 per 1000 population [1]. Decreased global renal blood flow, ischemia-reperfusion damage, and following renal tubular epithelial cell (TEC) death have been recognized as the prevailing pathophysiology of S-AKI, accumulating evidence suggests that additional mechanisms must be at play [5,6]. Inflammatory mediators, with either pathogen- or damage-associated molecular patterns, are released and bind to toll-like receptors on immune cells or renal TEC surfaces during sepsis, which increases oxidative stress, the production of reactive oxygen species (ROS), and mitochondrial injury [7,8]. S-AKI therapy, especially preventive therapy, remains reactive and non-specific as the pathophysiology has yet to be fully elucidated
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